S54 R. Chilengi / Acta Tropica 112S (2009) S53–S62
the research derives from having sought accepted medical care or
Box 1: Fundamental ethical principles and their appli- having been selected from the general public because of known or
cations in biomedical research. suspected abnormality (45CFR part 46, 2005, South African Medical
Principle Description Application Research Council, 1993).
Autonomy Human beings are born as Informed consent.
autonomous agents. This 2.2. When does research include human participation?
autonomy gives them rights to
self-determination that must be
respected. Autonomy demands The term research may be very general. Some studies which
that the wishes of all persons still qualifying as research, may not actually involve living human
must be respected and we do beings, but may be on samples or information obtained from
so by asking their opinion or humans. For example, research that involves tissue specimens,
willingness to get involved or
medical records, genetic material, behavioural and/or biomedical
Non-maleﬁcence “Primun non nocere” Latin Evaluate foreseeable assessments, and treatments. Consequently, ethical and/or legal
translation for ﬁrst, do no risks and minimize obligations to protect human participants also apply to research
harm. Research must primarily harm. that uses:
and actively seek not to do
harm regardless of the extent
• Bodily materials, such as cells, blood or urine, tissues, organs, and
of potential good that may
arise from the research. hair or nail clippings, even if the researcher did not collect these
Beneﬁcence While minimizing harm, Maximize beneﬁts materials.
research must be of beneﬁt to • Residual diagnostic specimens, including specimens obtained for
individuals and society at large.
routine patient care that would have been discarded if not used
Beneﬁcence is a group of
norms for providing beneﬁts, for research.
and balancing beneﬁts against • Private medical information, such as medical data that can be
risks and costs. readily identiﬁed with individuals, even if the information was
Justice A group of norms for Fair subject selection
not speciﬁcally collected for the study in question. Research on
distributing beneﬁts, risks and and fair distribution of
costs fairly. The beneﬁts of beneﬁts. cell lines or DNA samples that can be associated with individuals
research must equitably be falls into this category.
shared by those who bore the
cost and risk of the research. Social, economic and/or behavioural information for health
research purposes (Nufﬁeld Council on Bioethics, 1999).
2.3. Why must participants take responsibility?
It is important at this stage to emphasize that this paper has a
bias to speciﬁc guidelines for the conduct of clinical trials involved
The fundamental ethical principle of Justice requires “fairness”
in development of medicinal products.
or “entitlement”; it implies giving to each his/her due. Justice
requires that “equals be treated equally and un-equals unequally”
2. Participants (45CFR part 46, 2005). This means that human beings as moral
equals should be treated equally unless there must be a reasonable
In this paper, the following terms “participant, volunteer, and justiﬁcation for treating them differently. The principle of justice
subject” have been used interchangeably to mean the individual. demands fairness in the treatment of individuals and communi-
ties and the equitable distribution of the burdens and beneﬁts of
2.1. Who is the research participant? research. The extrapolation of the application of this principle is
that the “fruits of research must principally beneﬁt those that bore
The human participant is a living individual about whom (and the risks of the research”. In other words, humanity owes the enjoy-
includes specimen taken from them), a researcher obtains either: ment of health care to research, and as such to enjoy the outcomes
of research, individuals within our communities must bear the risk
(1) Data through intervention or interaction with the individual; of that research. This has important implications for such issues
or as choice of study population, recruitment into study, study and
(2) Identiﬁable private information (45CFR part 46, 2005). post-study beneﬁts, etc.
Secondly, the fundamental principle of autonomy requires that
In other words, this is the individual upon whom the investiga- the wishes and choices of an individual be respected (Belmont
tor performs research. In the course of participating in a research Report, 1979). The word autonomy comes from two Greek words:
study, a participant may provide information to investigators about nomos (“rule”) and autos (“self”), giving it the literal meaning of
other persons, such as a spouse, relative, friend, or social acquain- “self-rule” or “self-governance”. Autonomy implies an individual
tance. The information may be sensitive (e.g., regarding alcohol or who is master of himself/herself and can act, make free choices and
drug use, diet, or lifestyle) and personal. These other persons are take decisions without the constraint of another. Informed consent
referred to as “third parties.” Nevertheless, investigators should is a derived application of this principle such that an individual has
treat all research information about individuals as conﬁdential. the right to consent to take “risks” as long as they understand fully
Identifying information, whether about a human participant or a the implications of their choice. The necessary pre-conditions of
third party, should be kept secure and protected from inappropriate autonomy are thus, competence (the capacity to be a moral agent),
disclosure. and liberty or freedom.
Research may be done on participants who are either healthy Therefore, as autonomous beings, we inevitably assume respon-
or unwell. In this context, a healthy participant is one who is not sibilities for whatever choices we make, and this includes
known to suffer any illness relevant to the proposed study, and participation in research, provided the prevailing conditions enable
is within the ordinary range of body measurements. On the other the individuals to exercise their right to self-determination. For
hand, patient status refers to an individual whose participation in most studies to succeed, the research participant must comply to
R. Chilengi / Acta Tropica 112S (2009) S53–S62 S55
the requirements of the protocol, otherwise the set answers may and should be able withdraw participation should they ﬁnd that
not be fully answered. their interests are no longer satisﬁed by continued participation.
In resource constrained settings like Africa, this can be practically
2.4. What are the responsibilities of the participants? challenging as most participants are likely to continue in research
for want of options to obtain even the most basic of health care
There are numerous implied responsibilities of a participant in (Pool and Wenzel, 2005).
research. In this paper, they are summed into three main categories. The above issues notwithstanding, addressing responsibility
when it comes to research involving minors (dependent children
2.4.1. Responsibility to understand that this is research below legal age of responsibility) remains an ethical dilemma.
Participants must have a fair understanding of what research is. Although by default, parents and guardians are made to assume
In the context of clinical trials, it is akin to “experimentation”, and this responsibility, it is remains debatable whether this is the most
thus their choice to participate, after being given adequate infor- appropriate paradigm in view of the points raised above which,
mation and explanations, implies that they volunteer to be objects arguably, a minor cannot be accountable for. According to CIOMS
of that experiment. Participants must be aware that it is not an guideline 9; “When there is ethical and scientiﬁc justiﬁcation to con-
obligation to participate in the research and neither must it be a duct research with individuals incapable of giving informed consent,
pre-requisite to accessing routine medical nor other social services the risk from research interventions that do not hold out the prospect
publicly available. of direct beneﬁt for the individual subject should be no more likely and
If they understand and accept that the research is intended for not greater than the risk attached to routine medical or psychologi-
their own good and ultimately that of their community and society cal examination of such persons. Slight or minor increases above such
at large, they should thus, commit themselves to the success of that risk may be permitted when there is an overriding scientiﬁc or medical
research in as far as what is expected of the participants. In essence rationale for such increases and when an ethical review committee has
the success of the research is highly dependent on the cooperation approved them”.
of the participant in being available to meet the protocol activi- Guideline 10 further addresses the speciﬁcs of involving chil-
ties, provide information or specimens. It is however important at dren in research, to which an emphasis may be added: “There must
this point to note that there are key requirements for the informed be direct beneﬁt to the individual minor, and measures to minimize
consent process to be considered ethically sound, i.e. (1) there has the foreseeable risks must be categorically clear” (CIOMS, 2002).
to be adequate information shared; (2) the potential subject must
have competence; (3) there must be comprehension and (4) the
atmosphere must be free from coercive elements (45CFR part 46, 2.5. Community representatives
2005; World Medical Association, 2008). In contemporary times,
these responsibilities have been rightly weighed on the investiga- Communities constitute important stakeholders who must
tor; but it is however obvious that here remains a sufﬁcient share equitably participate in research. However, special attention must
of responsibility that the participant has to bare. be paid to particular categories of communities to avoid ill-formed
In situations where the participant is a minor or somehow perceptions based on cultural, social, spiritual or economic misun-
incompetent of giving informed consent, the parent or legally derstandings. “To misrecognise or fail to recognise cultural difference
acceptable guardian assumes this responsibility (World Medical can inﬂict harm, can be a form of oppression, imprisoning someone
Association, 2008; ICH-GCP E, 1997). (or a group) in a false distorted model of being- Research cannot be
difference-blind” (NHMRC, 2003). Case examples here include spe-
2.4.2. Responsibility for risk-beneﬁt analysis cial considerations for research involving the poorest communities
As autonomous beings, participants must be able to make judge- in sub-Saharan Africa, or Aboriginal Maori people of New Zealand,
ment of what risks they may be committing themselves to by san people of Kalahari desert or any other groups of human beings
accepting to participate in research. This is why “competence” is a who for historical or evolutionary reasons may be distinctly dif-
critical requirement, because the participants must be able to eval- ferent. Useful guidelines are available for advising engagement to
uation whether the risks they are taking are consistent with their such communities (NHMRC, 2003; HRC, 2008; Lavery et al., 2007;
own interest. The participant should be able to make judgement UNAIDS, 2007).
that their perceived beneﬁts of participation reasonably outweigh To ensure the ethical and scientiﬁc quality and outcome of
the clearly present and foreseeable risks of the research. In other proposed research, its relevance to the affected community, and
words, after having been given the necessary information by the its acceptance by the affected community, researchers and trial
researchers and time to ask questions, the prospective participants sponsors should consult communities through a transparent and
should weigh the risks and beneﬁts of participation before making meaningful participatory process which involves them in an early
a decision. and sustained manner in the design, development, implementa-
It is important to recognize the fact that in most under developed tion, monitoring and distribution of results (Molyneux et al., 2007).
communities, and especially for therapeutic research, the distinc- Community engagement may be arranged through local com-
tion between medical service and research is hard to make and munity leaders such as chiefs, community health workers, or
participants may not always be in a position to realize the impli- local civil authorities. Community Advisory Boards (CABs) are
cations of their choices. However, this is why structures exist to increasingly being established as a mechanism for community
re-enforce the protections by way of protocol approval process by engagement in research.
ethics committees and regulatory authorities. In general community representatives help to achieve commu-
nity engagement aimed at, but not limited to the following:
2.4.3. Responsibility to maintain right to autonomy
The research participant is primarily responsible for his or her
own safety and wellbeing. They must be able exercise their right • Ensuring that communities buy into the relevance of research;
to withdraw their voluntary participation in the research when • Enhancing cultural and practical acceptability;
they perceive that their interested may be in jeopardy at any stage • Community ownership, responsibility and authority;
during the research. They are therefore responsible for contin- • Minimizing community disruptions on major activities and cul-
uous evaluation of their commitment to participate in the trial tural norms;
S56 R. Chilengi / Acta Tropica 112S (2009) S53–S62
• Avoid exploitation bearing the perspectives of the lay commu- Medical Association, 2008; 45CFR part 46, 2005; CIOMS, 2002). The
nity; researcher’s principle obligation is to promote the safety and well
• Avoid unfair distribution of beneﬁts of research; and being of the participants and this entails that research involving
• Take into account social, cultural and political hazards human participants is only justiﬁable if the beneﬁts of participation
outweighs the foreseeable risks.
The spirit of this paper is to stimulate debate and discussions Less emphasized and worth pointing out is the Helsinki point 17
that will lead to development of guidelines and sets of responsi- speciﬁcally singles out research in vulnerable populations which
bilities for such community organs. Surely, in order to hold such must be responsive to the health needs of that population and
key positioning in research, it must come with some clarity on . . . “reasonable likelihood that the community stands to beneﬁt from
responsibilities as well. the results of the research” (World Medical Association, 2008). This
implies that the investigators must make a reasonable evaluation
3. Researchers [investigators] to ensure that there is some foreseeable beneﬁts primarily to the
participants and, or their communities. Implicit in this guidance is
A researcher is the individual who undertakes the study. This an obligation to the investigator to negotiate and ensure that the
term may be used synonymously with “investigator”, who accord- research being proposed somewhat meets this requirement. Fur-
ing to GCP is: the person who takes responsibility for the conduct ther, CIOMS 10 requires the sponsor and the investigator to make
of the trial or study and the study site (ICH-GCP, 1997). This paper every effort to ensure that (i) the research is responsive to the health
has not taken the regular approach of listing the responsibilities, needs and the priorities of the population or community in which it
but has focussed on the fundamentals and proposes categorisation is to be carried out, and (ii) any intervention or product developed,
of these responsibilities as owed to the various stakeholders. or knowledge generated, will be made reasonably available for
the beneﬁt of that population or community” (CIOMS, 2002). One
3.1. Intrinsic responsibility to self apparent mechanism to ensure that these complex responsibilities
are met is by following recommendations on community consulta-
An investigator ought to be conscientious. An investigator ought tion and engagement (Nufﬁeldbioethics, 2005; CIOMS, 2002; World
to be qualiﬁed by training and experience in the speciﬁc ﬁeld of Medical Association, 2000).
research (ICH-GCP, 1997). This is applicable to any type of research
that an investigator may want to undertake. For instance, if one 3.3. Responsibility to local authorities
wants to conduct behavioural research, they must have qualiﬁca-
tions in the relevant social sciences ﬁeld. In the case of physicians Investigators are hired and paid to conduct research following
wanting to conduct medical research, the Declaration of Helsinki the legally approved norms and regulations in a country. The ICH-
stipulates that “it is the duty of the physician in medical research GCP guidelines speciﬁcally raise responsibilities of the researcher
to protect the life, health, privacy, and dignity of the human subject. to the local regulations and the authorities including:
The physician’s knowledge and conscience are dedicated to the ful-
ﬁlment of this duty” (World Medical Association, 2008). ICH-GCP • To understand and conduct their work according to the applicable
adds that “the investigator should be qualiﬁed by education, train-
ing, and experience to assume responsibility for the proper conduct of • To observe any law(s) and regulation(s) addressing the conduct
the trial, should meet all the qualiﬁcations speciﬁed by the applicable
of clinical trials of investigational products;
regulatory requirements” (ICH-GCP, 1997). The physician may com- • To adhere to all study related requirements, Good Clinical Practice
bine medical research with medical care, only to the extent that
requirements, and full compliance to approve protocols;
the research is justiﬁed by its potential prophylactic, diagnostic or • Ensure that the Ethical Committee has approve the research
therapeutic value. When medical research is combined with med-
before it is implemented
ical care, additional standards apply to protect the patients who • Provide direct access to records and permission to examine,
are research participants. The investigator should be thoroughly
analyse, verify, and reproduce any records and reports that
familiar with the appropriate use of the investigational product(s),
are important to evaluation of a clinical trial. Any party (e.g.,
as described in the protocol, in the Investigator’s Brochure, in the
domestic and foreign regulatory authorities, sponsor’s moni-
product information and in other information sources provided by
tors and auditors) with direct access should take all reasonable
the sponsor (ICH-GCP, 1997).
precautions within the constraints of the applicable regulatory
It is a particularly important responsibility for the investigator to
requirement(s) to maintain the conﬁdentiality of subjects’ iden-
introspect on whether they have sufﬁcient time to properly conduct
tities and sponsor’s proprietary information.
and complete a study and ensure that s/he has adequate resources
to meet the requirements of the study. The CIOMS guideline 8
(2008) stipulates that “the investigator must ensure that potential 3.4. Responsibility to the global scientiﬁc community
beneﬁts and risks are reasonably balanced and risks are minimized”.
Guideline 9 emphasizes extra caution when dealing with vulnera- The main objective and deﬁnition of scientiﬁc research is to col-
ble people. lect, analyse and interpret data that should contribute to a body
Lastly on this point, the publication of research ﬁndings must of generalizable information (45CFR part 46). It is important that
observe ethical norms. Helsinki Declaration, principle 30 states: “In research ﬁndings be published, whether positive or negative so that
Publication of the results of research, the investigators are obliged to the global scientiﬁc community can have access to the data. Further,
preserve the accuracy of the results; negative as well as positive results individual researchers owe it to the global community to conduct
should be published or otherwise be made publicly available”, (World their work in an ethically acceptable manner for the following rea-
Medical Association, 2008). sons:
3.2. Responsibility to the participants and community • Generation of knowledge is critical to answering the health needs
of the global community. Therefore, researchers are morally
There are duties that are explicitly stated, and others are implied obliged to contribute to the alleviation of disease and other vices
within international research guidelines (ICH-GCP, 1997; World affecting the human population in general.
R. Chilengi / Acta Tropica 112S (2009) S53–S62 S57
• Resources available for research globally are limited. Therefore, Laboratories should be sufﬁcient for observing key good labora-
individuals accessing these resources have a moral obligation to tory practice requirements. Equipments need regular maintenance
ensure that the resources are used in the best way possible; and documentation of their performance. Laboratory certiﬁcation
• Biomedical research needs to continuously be justiﬁed through through external proﬁciency testing schemes and accreditation is
the beneﬁts that come out of it. Negative results should particu- desirable for excellence in research. Further, it is desirable that
larly be also publicized to help other research groups who may institutions set up quality systems including internal monitors who
be pondering on the same or similar research questions. This will regularly ensure that the institutional quality assurance pro-
helps avoid further experimentation on human subjects when gramme is functional.
scientiﬁcally important questions have already been answered. Transportation for staff and participants should be operated
observing institutional policies. Vehicles and ambulances should
4. Research institutions be maintained in good functional state and this is best handled
at institutional level and should not be dependent on individual
Research institutions have particularly escaped the responsibil- projects. This is because some poorly funded projects run the risk
ity lists described in most guidelines. Research takes place, and of compromising the institution’s reputation.
should only be allowed through bonaﬁde institutions that are
nationally recognized and mandated to undertake research within 4.3. Ethical review
their localities. In the case of non-governmental organizations, very
clear mandates should be in place that holds such institutions Institutions must ensure that all research undertaken under
accountable to the public system in order to ensure protection of their umbrella is appropriately reviewed and approved. It is the
the interests of the wider public, and most importantly vulnerable responsibility of any institution allowing research to take place,
participants. to also ensure that appropriate ethical review mechanisms are in
Thus there should be institutional regulations or guidelines as place; either as institutional review boards, independent review
well as checks and balances to protect the reputation of the insti- committee or national ethics review committees.
tution. Where the committee is institutional, the institution must
ensure that sufﬁcient infrastructure exists and that the core oper-
4.1. Staff related responsibilities ations are supported to facilitate efﬁcient procedure. Other details
pertaining to operations and responsibilities of ethics committees
Institutions must conform to local laws pertaining to hiring staff, are addressed later in this paper.
conditions of service, and other fringe beneﬁts applicable to its staff.
In the context of developing countries, it is highly desirable that 5. Sponsor
institutions ensure a staff development plan that would allow pro-
gressive career development. The institution should ensure that According to the ICH-GCP guidelines in sections 1.53 and 1.54
adequate staff are in place to ensure that the research studies the sponsor is deﬁned as “an individual, company, institution, or
are efﬁciently conducted while observing legal requirements on organization which takes responsibility for the initiation, man-
working hours and staff leave needs. The ethical imperative here agement, and/or ﬁnancing of a clinical trial”. (ICH-GCP, 1997). An
is that the institution needs to ensure that staff hired to serve on investigator is an individual who both initiates and conducts, alone
research studies are appropriately qualiﬁed for their roles; wher- or with others, a clinical trial, and under whose immediate direc-
ever indicated, institutions must be able to check that staff belong to tion the investigational product is administered to, dispensed to,
appropriate professional bodies that ensure that conduct is within or used by participants. The obligations of a sponsor–investigator
the expected professional norms. The institutions must also ensure include both those of a sponsor and those of an investigator. The
that local labour laws are understood and observed and appropriate European Directive, cognizant of the potential importance of such
administrative support is rendered to investigational staff. non-commercial studies, makes provision for simpliﬁed good man-
The sponsor is obliged to provide indemnity cover for trial ufacturing practices conditions to accommodate such studies while
related eventualities (ICH-GCP, 1997). It remains the responsibil- upholding the quality standards (EU Directive, 2001).
ity of the institution to ensure that appropriate insurance policy The ethical imperative that constitutes a fundamental obliga-
cover is in place for professional indemnity on the institution and tion for sponsors is the protection of the safety and well being
its researchers. of actual and potential research participants. The detailed spon-
sor responsibilities are ably addressed in the guidelines, however
4.2. Infrastructure related responsibilities for the purposes of this paper key sponsor responsibilities into ﬁve
It is the duty of the institution to ensure that their infrastruc-
ture is adequate to support the research being conducted within the 5.1. Responsibilities to the funding authorities/shareholders
institution. The administrative structure should be able to provide
up to date ﬁnancial structure to internationally acceptable account- It is important to emphasize that companies that sponsor
ing standards to support research. The Administrative structure research are primarily employed to earn revenue for their share-
must be able to offer legal guidance to investigators especially for holders. Thus, in whatever they do, it is important for the survival of
dealing with contracts and other inter-institution agreements. their companies to ensure that sound decisions are made and these
When product research is involved, it is the duty of the insti- may not always be based on purely moral considerations. The crit-
tution to ensure that sufﬁcient systems are in place to observe ical issue is to ensure that when sponsors meet the expectations of
both good clinical practices and good laboratory practices. This has their shareholders and internal company policies, the research par-
implications of ensuring that institutional policies address quality ticipants must not be unduly exploited. In essence, we need to ﬁnd
control and quality assurance process. To undertake phase I studies, a good balance between the company’s proﬁt making nature, and
the institution must ensure that at a minimum, emergency facili- ethical considerations of their research and developmental activi-
ties with resuscitators are in place. Further, appropriately qualiﬁed ties.
physicians and nurses must be trained and regularly updated on However, there are now many not-for-proﬁt sponsors of
emergency medicine. research, especially that funded through the public sector, philan-
S58 R. Chilengi / Acta Tropica 112S (2009) S53–S62
thropies and charity organizations. When organizations sponsor mended that sponsors deal directly with the ethical review boards,
research in this context, requirements of the funding organizations but they must do so through their investigators. They must ensure
must be fulﬁlled. The common arrangement requires that the bene- that before the study can be allowed to start, adequate review and
ﬁciary organization takes on all sponsor related responsibilities and approval has been done by the legally mandated bodies both locally
ensure that the funding authority is clearly free from any potential and internationally.
litigations that may arise from the research.
5.2. Responsibilities to participants and their communities 5.5. Data safety monitoring boards [DSMBs]
The fundamental obligation of sponsors to the participants and The DSMB is a relatively new phenomenon in clinical trials. It
communities is to ensure that the research is safe, and that the is described as “a body of selected experts that monitors regularly
beneﬁts of participating in such research outweigh the potential data from a clinical trial, review and assesses the performance of
risks of doing so. CIOMS guideline 10 speciﬁcally insists that all its operations, and makes recommendations as appropriate to the
proposed research must be both responsive to the health needs of sponsor” (ICH-GCP, 1997; Lang et al., 2008). Their focus is on safety
the communities where it is to be done, and must also show that the data, and their interim data reviews are done in the context of the
knowledge generated or product developed will be reasonably be most recent scientiﬁc literature. Other terminologies are used for
made available to those communities (CIOMS, 2002). This is par- the same concept such as Safety Monitoring Committee (SMC), and
ticularly important in the developing world where typically, the Independent Monitoring Committee (IDM).
research participants are vulnerable in many ways. Careful consid- The DSMB may be established by the sponsor to assess at inter-
eration is required to ensure that the beneﬁts of the research do vals the progress of a clinical trial, the safety data, the critical
not otherwise unduly inﬂuence the decision making process of the efﬁcacy endpoints, and to recommend to the sponsor whether
communities and participants to be involved in research. to continue, modify, or stop a trial (ICH-GCP 1.25). Guidance on
Three of the four fundamental ethical principles (beneﬁcence, operations and requirements of DSMBs are still emerging and a
non-maleﬁcence and justice) all require that research leads to ben- comprehensive account of Lang et al. recommends the following
eﬁts for those who participate while potential risks be minimized situations to have DSMBs:
as much as possible. This is a fundamental obligation; however,
caution is advised when considering this matter which should be • Randomized control trials (RCT) evaluating clinical efﬁcacy and
handled on a case by case basis because of the complex impli- safety of an investigational new product;
cations and variable socio-economic conditions. The local ethical • Controlled trials with mortality or severe morbidity as a primary
review committee must play a key role in evaluating the proposed or secondary endpoint;
beneﬁts against the likelihood of coercion to participate in the • Early studies of a high risk new intervention;
research. • Clinical trials where the design or data accrual is complex;
• Where there is uncertainty about whether the data will lead to
5.3. Responsibilities to investigators and their institutions changes in the trial design;
• Products or interventions being used as a new combination
Sponsors also have speciﬁc obligations to the investigators and • Products that are unlicensed or used off label (outside marketed
research institutions. The GCP has detailed responsibilities out- indication);
lined, including selection of investigators, ensuring quality systems, • Trials involving vulnerable populations such as children, preg-
provision of product and information, provide for patient care, nant women, and mentally impaired or very sick participants;
insurance and sufﬁcient monitoring of the research protocols for • Studies carried out in emergency situations; and
compliance (ICH-GCP, 1997). • Studies where data may justify early terminations, especially for
The sponsor must provide sufﬁcient funding to undertake the safety reasons.
research well. From an ethical perspective, enough budget must be
allocated for patient care, medical and laboratory consumables, and
ensure state of the art equipment for evaluation of safety parame- The terms of reference and details guiding the operations of
ters. Further, the sponsor must ensure that there are sufﬁcient care the DSMB should normally be articulated in a DSMB Charter. The
facilities to deal with detection, reporting and treatment of medical Charter may be made available to ethics committees and regula-
emergencies. tory authorities as may be required. Indeed some local authorities
It is also critical for sponsors to ensure that no conﬂict of interest do require submission of the DSMB reports for their review. This
exists when investigators are selected, and nearly all collaborative is especially so in complicated trials where the local authori-
research currently includes signing ofﬁcial statements to attest a ties may not have the competence to review the progress of the
lack of ﬁnancial or other interests between the investigators and study. The DSMBs are generally empowered to review the ongo-
the sponsor organizations. ing progress of the trial and may make recommendations to the
sponsor for continuation, modiﬁcation or even termination of the
5.4. Responsibilities to the local authorities study.
A recurrent ethical debate around establishment of DSMB is
A critical requirement is to ensure adequate reporting of safety around their independence and whether the DSMB statistician
related matters to applicable Regulatory Authorities. As far as the should be totally independent or part of the study, and frequencies
GCP guidelines are concerned, “applicable Regulatory Authorities” of interim analyses (Lang et al., 2008; Hrobjartsson et al., 2007).
are given the utmost and ﬁnal say on what must be observed. In Given the current convention, it is the responsibility of the spon-
general, it is considered that the sponsor must seek to fulﬁl all sor, and the members of DSMBs (individually and collectively) to
the regulatory requirements both internationally and locally. Early ensure that the DSMB is really independent in decision making and
engagement and negotiation is recommended to allow for sufﬁ- operate in the best interest of study participants’ safety. Regula-
cient time to meet requirements before the study can begin. tory authorities, investigators as well as ethics committees are also
The ethical review requirements are another part that the better placed to counter check and ensure that the DSMB meets its
sponsor must be fully aware of and be able to satisfy. It is not recom- objectives.
R. Chilengi / Acta Tropica 112S (2009) S53–S62 S59
6. Regulatory authorities [RAs] The two WHO guidelines have addressed in depth, the descrip-
tion of what ERB are, or are intended to be, recommended
RAs are agencies that regulate medicines and are often referred compositions, what ethical review entails, how they should oper-
to as Medicines Regulatory Authorities/Agencies (MRAs). These ate, reach decisions and communicate those decisions. Other
may be national or supranational organizations established and publications have ably provided ethical framework for evaluating
mandated to formulate and implement laws that regulate the whether proposed research is ethical (CIOMS, 2008; Emmanuel et
business of medicines. RAs are established by local or regional al., 2000; Amdur and Elizabeth, 2002). In this paper a composite
governments or authorities to be able to address the following view of looking at the responsibilities of ethics committees due to
important medicines related matters: research participants, investigators, sponsors and local authorities
• Set and enforce standards or regulations for product quality, man-
ufacturing (GMP) and marketing;
• Review evidence (data) needed to approve a medicinal product; 7.1. Responsibilities to the participants
• Review and regulate research and development of medicines
Perhaps the greatest role of the ERB is to ensure that research
especially in terms of GLP and GCP;
• Labelling reviews and product promotion regulation; that is conducted among the communities that the committee rep-
• Review and approve research studies aimed at developing spe- resents is ethical. This statement is loaded with all the details
described in various guideline documents listing the various roles
ciﬁc medicinal products;
• Provide a mechanism for safety evaluation of approved medicinal and responsibilities. Critical to this obligation is to ensure that in
its basic setup, composition, operations and follow up activities are
such that the mandate of protecting research participants is car-
ried out effectively. As research participants are often times, of low
The key objective is to protect consumers/public against hazards socio-economic status and of low literacy rates, especially in Africa,
associated with consumption of the medical products. RAs provide this responsibility is even heavier than it could be if the participants
pre-market review of data assembled in support of applications for were less vulnerable. In many respects, this responsibility is similar
market authorization to determine whether developers have tested to representing the “voiceless”. It could be argued in most research
and established sufﬁcient evidence for quality, safety and efﬁcacy contexts that it is difﬁcult for the target research participants to be
for the intended use of the candidate product before granting mar- able to actually read, comprehend, analyse the risk posed by pro-
ket authorization. They provide market controls and licensing of posed studies in order to make sound decisions on participation in
medicines, import/export certiﬁcation, inspections, surveillance, the research.
and control of promotion. RAs are mandated to take legal actions In some worst case scenarios prevailing in some developing
including suspension or revocation of authorizations and arraign- countries, the participants are so vulnerable that it is actually
ment in courts of laws. “nearly impossible” for them to be able to even consider refus-
In so far as medical research is concerned, RAs hold the supreme ing what researchers bring to them by way of research studies. In
authority over the conduct of research under their jurisdiction. The such setups informed consent documents signed may not actually
GCP guidelines subjugate the ﬁnal decision making and speciﬁc mean the participants understand and accept the research. They
positions to the RAs (ICH-GCP, 1997). All other guidelines approach may be willing to participate for many other reasons more impor-
regulatory authority with similar absolute decision making posi- tant to them than the risks posed by the research. In the light of the
tioning with the exception of the European Directive on clinical above therefore, this paper proposes that the ethics committees
trials that seems to provide some instructions to the member state and its membership, individually and severally have the follow-
authorities (EU Directive, 2001). ing moral obligations within the currently prevailing biomedical
A case is made here for some set of regulations or guidelines research setup.
for the RAs to be held by. Indeed other voices of decent have crit-
icized both the ICH-GCP guideline as well as the authority of the
US-FDA (Goodyear et al., 2009; Grimes et al., 2007). In the interest • The members must be qualiﬁed by training or role for which they
of fairness and accountability, it might be good for the interna- are nominated to serve on the committee. Each member must
tional community to come up some with sets of responsibilities that have a speciﬁc function for which they are nominated to serve
would help set borders for RAs. It is particularly important for RAs and fulﬁlling that role must be the “moral” obligation owed to
set in developing countries where, in the absence of full capacity to participants and the research community they represent.
meet their obligation, the authorities are moving towards enforcing • Members must ensure that they review protocols to the best of
all the powers attributed to them from the international guidelines. their abilities in order to protect the participants against the risks
Much authority must be complementary with much responsibility that research may otherwise pose;
and accountability; otherwise, there is a risk of that authority being • Corporately, the ERB must ensure that in its operations, safety
misused or indeed abused. and well being of participants is of primary concern. This entails
establishing procedures and mechanisms that require investiga-
tors and sponsor to meet standards that satisfy and enhance the
7. Ethics committees protection of the well being of participants.
• Oversight activities must be in place to ensure that the research
There are many synonyms for committees that review biomed- that is approved is actually what is implemented. This oversight
ical research protocols, but for the purposes of this paper, should include review of progress reports, safety issues arising
terminologies are loosely used to mean the organ reviewing and from ongoing trials and actually physical follow up.
approving biomedical research to safeguard the dignity, rights,
safety, and well being of actual or potential research participants
(WHO, 2000; Tedlock, 1983). Terms such as Independent Ethics If committees fulﬁl these kinds of responsibilities, healthy
Committee (IEC), Institutional Review Boards (IRB), Institutional research environments would be promoted through which rele-
Ethics Committee (IEC), National Ethics Committee (NEC), and vant research is promoted while unethical elements are detected
Ethics Review Boards (ERB) are interchangeably used. and dealt with appropriately.
S60 R. Chilengi / Acta Tropica 112S (2009) S53–S62
Fig. 1. Interrelations among key players. The schematic representation of the interactions of the players. The arrows generally show the communication lines, ﬂow of
information or reports.
7.2. Responsibilities to investigators and their institutions research community interests are duly addressed through diverse
representation on the ethical committee.
By virtue of their role in the proposed studies, investigators The ERB must have clear procedure and requirements. This
have a certain level of inevitable bias. It is the responsibility of the allows the sponsors of research to be able to take care of the condi-
ERB to ensure that the research proposed is thoroughly reviewed, tions set by the ERB. Transparency is another important obligation
not only to protect the participants, but also to improve the work especially owed to sponsors. It must be clear what issues the ERB
of the investigators. The ethical approval should actually protect considers and reasons for non-approval of proposed studies must
the investigator and the institution to the extent that unfore- be satisfactory. Conﬂicts of interest must clearly be addressed in
seen problems can be publicly acceptable when they occur within a manner that decision making may not be inﬂuenced unduly by
approved studies. The ethics committee is thus obligated to review whatever the conﬂicts may be. In short, ethics committees must
all information that the investigators would use in communicating have documented clear requirements, standard operating proce-
to potential participants including advertisements, informed con- dures, composition, schedule of meetings, and transparency in its
sent forms, protocols, information collection tools etc. It would be routine operations.
very helpful to investigators if ERBs served as an additional eye to Further, the ethics committee must provide assurance that the
ensure that they do not allow scientiﬁc interests to blind them to research that they approach is actually what goes on in the ﬁeld and
potential ethical pitfalls. that they have mechanisms to detect defaulting investigators and
The scientiﬁc aspects of research are also of key importance. have ability to enforce the required disciplinary actions in those sit-
According to the Declaration of Helsinki, bad or poor science uations. In the absence of this capability, chances of both scientiﬁc
is also unethical (World Medical Assembly, 2008). Thus, ethical and ethical misconduct remain very high.
review systems must ensure that the science proposed is sound,
by whatever mechanisms that may be available to the ERB. Some
7.4. Responsibilities to the local authorities
institutions have separate scientiﬁc review before ethical review
while others have combined scientiﬁc and ethical review (WHO,
It has to be clear that ERBs also serve the public interest within
2000; Tedlock, 1983).
the local contexts that they are established. Thus, it is of primary
importance that the ERB draws its mandate from the local author-
7.3. Responsibilities to sponsors ities. It is desirable that a legal basis for the ERB establishment is
enshrined within the local laws such as Acts of Parliament or other
Part of the reason for the requirement that ERBs are multi- speciﬁc legal frameworks.
disciplinary is to ensure that the key group interests are International laws such as the Universal Declaration of Human
represented (WHO, 2000). In most situations, the sponsor cannot Rights of December 1948 speciﬁcally provide some protection to
realistically be close enough to the community to really under- all human beings (United Nations, 1948). The General Assembly of
stand local values and norms. In this regard, ERBs should show the United Nations adopted and proclaimed the Universal Declara-
that the interests of the community they represent are well taken tion of Human Rights. One of the articles stipulates that ‘all human
care of and this would provide assurance to the sponsors that beings are born free and equal in dignity and rights, and no one shall
the chances of unethical conduct are minimal because the local be subjected to torture or to cruel, inhuman or degrading treatment
R. Chilengi / Acta Tropica 112S (2009) S53–S62 S61
or punishment’. These human rights are at an international level Beauchamp, L.T., Childress, F.J., 2001. Principles of Biomedical Ethics, Fifth Edition.
which may be inaccessible to research participants some of whom Oxford University press.
Belmont Report: Ethical Principles and Guidelines for Research involving Human
may be poor and vulnerable. Thus ERBs operating within local legal Subjects. The National Commission for the Protection of Human Subjects of
framework could be an immediate mechanism of protecting the Biomedical and Behavioural Research, April 8, 1979.
interests of research participants. Code of Federal Regulations title 45- Public welfare Department of
Health and Human Services, part 46 protection of human sub-
The ERBs must also be answerable to a higher authority within jects. 2005; available on http://www.hhs.gov/ohrp/documents/
the local setup. An example from the US shows that the Department OHRPRegulations.pdf.
for Health and Human subject Research oversees the operations of Chilengi, R., 2009. Clinical development of malaria vaccines: should earlier trials be
done in malaria endemic countries? Hum. Vaccines 5 (9), 1–10.
ERBs and has direct links to the FDA. This is a major gap in most Emmanuel, E., Wendler, D., Grady, C., 2000. What makes clinical research ethical?
developing countries, where there is no ﬁrm oversight on opera- JAMA 283, 2701–2711.
tions of ERBs (Nyika et al., 2008). International guidelines could also EU Directive, 2001/20/EC. Clinical trials directive by the European Parliament and
the Council of the European Union.
be more prescriptive on the speciﬁc responsibilities of ethics com-
Hrobjartsson, A., Forfang, E., Haahr, M.T., Als-Nielsen, B., Brorson, S., 2007. Blinded
mittees by which they should be held accountable to balance the trials taken to the test: an analysis of randomized clinical trials that report tests
huge mandate allocated to them. for the success of blinding. Int. J. Epidemiol. 36, 664–665.
Goodyear, M.F D.E., Trudo, L., Dominique, S., GodfreyF T., 2009. Does the FDA have
the authority to trump the Declaration of Helsinki? BMJ 338, b1559.
8. Concluding remarks Grimes, D., Hubacher, D., Nanda, K., Schulz, N., Moher, D., Altman, D., 2007. The Good
Clinical Practice guideline: a bronze standard for clinical research. Lancet 366
Although experimentation on human subjects is undesirable ICH-GCP E6, 1997. International Conference on Harmonisation Guidance: Good
(and clinical trials are a form of human experimentation), there Clinical Practices. Global Medical Education and Development. Available at
is no other way to develop knowledge and disease alleviating tools http://www.icr-global.org.
Health Research Council of New Zealand, 2008. Guidelines for Researchers on Health
for medical practice. None of the animal models is sufﬁciently rep-
Research Involving Maori.
resentative of the human, and a number of interventions tested in CIOMS International Ethical Guidelines for Biomedical Research Involv-
animals have repeatedly yielded disappointingly different results ing Human Subjects. Revised draft, January 2002; available on
in humans (Chilengi, 2009). Therefore, although animal models will
always provide important information, research in humans is cur- Lang, T., Roma, C., Ramadhani, A.N., Bernhards, O., James, E.T., Wen, L.K., Geoffrey,
rently inevitable; however, it must be directed by internationally A.T., 2008. Data safety and monitoring boards for African clinical trials. Trans.
accepted guidelines. Royal Soc. Trop. Med. Hyg. 102, 1189–1194.
Lavery, V.J., Grady, C., Wahl, R.E., Emmanuel, J.E., 2007. Ethical Issues in International
As we apply the fundamental ethical principles it is important to Biomedical Research: A Case Book. Oxford University Press.
strike reasonable balances. The dimensions of these moral princi- Molyneux, C.S., Peshu, N., Marsh, K., 2007. Trust and informed consent: insights from
ples (in range and scope) needs to be carefully balanced (in weight community members on the Kenyan coast. Soc. Sci. Med. 61, 1463–1473.
National Health & Medical Research Council of New Zealand, 2003. Values and
and strength) (Beauchamp and Childress, 2001). The four principles Ethics: Guidelines for Ethical Conduct in Aboriginal and Torres Strait Islander
being equally important, do not always carry the same weight and Health Research.
scope at all times. For example, little children and other individuals Nufﬁeld Council on Bioethics, 1999. The ethics of clinical research in devel-
oping countries, available on http://www.nufﬁeldbioethics.org/ﬁleLibrary/
with diminished capacity cannot have their right to autonomy at pdf/clinicaldiscuss1.pdf.
the same scale as non-maleﬁcence; likewise, beneﬁcence cannot be Nufﬁeld Council on Bioethics, 2005. The ethics of research related to health-
applied with the same weight among vulnerable subjects as those care in developing countries: a follow up discussion paper, available
on http://www.nufﬁeldbioethics.org/ﬁleLibrary/pdf/HRRDC Follow-
socio-economically well off. Thus, there is need to judiciously con-
up Discussion Paper001.pdf.
sider the implications of how we translate these ethical principles Nyika Aceme, Wenceslaus Kilama, Tangwa, G.B., Roma Chilengi, Paulina Tindana,
lest we completely override justice while trying to uphold the oth- 2008. Capacity building of ethics review committees across Africa based on the
ers (Lavery et al., 2007). Over enthusiastic enforcement of guideline results of a comprehensive survey. Developing World Bioethics, 1471–8731,
may ultimately be harmful to science and progress in research. Pool Robert, Wenzel Geissler, 2005. Medical Anthropology Text Book.
In this manuscript, the most commonly cited international South African Medical Research Council, 1993. Guidelines on ethics for medical
guidelines have been reviewed, assimilated and key players identi- research.
Tedlock, D., 1983. Surveying and Evaluating Ethical Review Practices: The spoken
ﬁed together with their respective roles and duties. Rather than the word and the work of interpretation. University of Pennsylvania Press, Philadel-
conventional listing of responsibilities, this paper has attempted phia.
to interpret the responsibilities in the light of fundamental ethical UNAIDS, 2007. Good participatory practice guidelines for biomedical HIV prevention
principles and pulled them together into concise and targeted sets United Nations, 1948. Universal Declaration of Human Rights. Available at
of core responsibilities to other stakeholders within the matrix of http://www.un.org/en/documents/udhr/.
complex stakeholder inter relations in research settings (Fig. 1). World Health Organization, 2000. Operational guidelines for ethics com-
mittees that review biomedical research, available on http://apps.who.
Particular efforts have been made to identify the key players int/tdr/svc/publications/training-guideline-publications/operational-guide-
whose responsibilities are less apparent and suggestions made as to lines-ethics-biomedical-research.
what could be some of their key responsibilities. Notably, all guide- World Medical Association, 2008. Declaration of Helsinki. Ethical principles for
research involving human subjects. Adopted by the 52nd WMA General Assem-
lines correctly allude to research participants as the victims (or
bly, Seoul, South Korea.
potential victims) to be protected and must beneﬁt from research;
however, they fail to identify any responsibilities at all for these
key players. Glossary
45 CFR: Code of Federal Regulations of the Unites States of America. Part 45 deals
Acknowledgements with regulations governing protection of human subjects involved in biomedical
I am grateful to Aceme Nyika and Vicki Marsh for critical review CIOMS: Council of the International Organization of Medical Sciences. The organi-
and advice on this manuscript. zation provide guidance on research ethics with particular bias towards less
DSMB: Data Safety Monitoring Board. This is an independent board set up by the
References sponsor of a trial to provide continuous review of safety matters and advise the
sponsor on continuation of the study.
Amdur, R, Elizabeth, B, 2002. Institutional Review Board: Management and Func- ERB: Ethics Review Board. This is a committee or board that reviews proposals of
tions. Jones and Bartlett Publishers. biomedical research and provides approval when due safety and well being of
S62 R. Chilengi / Acta Tropica 112S (2009) S53–S62
potential participants is well addressed. Used here interchangeably with sev- GMP: Good Manufacturing Practice. International guidelines for the pharmaceutical
eral similar acronyms including: IEC for Independent Ethics Committee, IRB for manufacture of medicinal products.
Institutional Review Boards, IEC for Institutional Ethics Committee, and NEC for ICH: International Conference on Harmonization. The landmark conference that lead
National Ethics Committee. to development and adoption of the GCP guidelines.
EMEA: European Medicinal Agency. The international regulatory authority that over- RCT: Randomized Controlled Trial. A design of clinical research where study subjects
sees development of medicinal products within Europe. are randomly allocated to one or the other arm of the study.
EU Directive: European Union Directive. Law passed by the European parliament RA: Regulatory Authority. Government or regional bodies established to regulate the
governing aspects of clinical research and product development. development and licensure of medicinal products.
FDA: Food and Drugs Authority. The United States of America regulatory authority. UNAIDS: United Nations programme on HIV/AIDS
GCP: Good Clinical Practice. International guidelines for the conduct of clinical trials. WHO: United Nation’s World Health organization.
GLP: Good Laboratory Practice. International guidelines for laboratories that support
environmental, animal and biomedical research.